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Synthesis and NMR Spectral Characteristics of Bisnorargemonine Isomers
butyl phthalate) as plasticizers in medically used devices, the question arises as to the potential danger t o the human reproductive process from plasticizers leached from these devices by blood or parenteral solutions. While the doses of di-2-ethylhexyl phthalate employed in this study were greatly in excess of the 5-7 mg. which have been reported in whole blood stored in di-2-ethylhexyl phthalate-plasticized blood bags (3), the possible cumulative nature of the plasticizer in the body must also be considered. Jaeger and Ruhin ( 3 ) found from 2.5 to 27 mg. % (dry weight) of this plasticizer in tissues of patients who were known to have received blood transfusions; in addition, they found that while the perfused rat liver could hydrolyze the plasticizer butyl glycolylbutyl phthalate, it did not hydrolyze di-2-ethylhexyl phthalate but tended to sequester and accumulate it. Further investigations are needed to determine the fate of these small, hut possibly repeated, quantities of plasticizers that may enter the patient as a result of medical or surgical treatment and to determine what, if any, efTect on reproduction or other physiological processes may result.
REFERENCES ( I ) A. S. Trimble. B. S. Goldman, J. K. Yao, L. K. Kovats, and W. G . Bigeloa, Surgcry, 59, 857( 1966). (2) W. L. Guess, J. Jacob, and J. Autian, Drug Intel., 1, 120 (1967). ( 3 ) R. J. Jaeger and R. J. Rubin, Science, 170,460(1970). (4) W. L. Guess, S. Haberman, 1). F. Rowan, R. K. Bower, and J. Autian, A m w . J . Hosp. Pliurni., 24, 494(1967). ( 5 ) S. Haberman, W. 1.. Guess, D. E‘. Rowan, R. 0. Bowman, and R. K . Bower. S P E (Soc. Plusf. Eng.) J . , 24, 62( 1968). (6) K. K. Bower. S. Haberman, and P. D. Minton,J. Phurmacol. Erp. Thvr., 171, 314(1970). (7) “The Merck Index,” 8th ed., Merck & Co., Inc., Rahway, N. J., 1968. (8) H. C . Hodge. Proc. Soc. Exp. Biol. Mcd.. 53, 2q1943).
(9) C. B. Shaffer, C. P. Carpenter, and H. F. Smyth, Jr., J . Ind. Hyg. Toxicol., 27, 130( 1945).
(10) J. H. Draize, E. Alverez, M. F. Whitesell, G. Woodard, E. C. Hagan, and A. A. Nelson, J. Pliurmacol. E.up. Tlier., 93, 26 (1948). ( 1 1 ) C. P. Carpenter, C. S. Weil. and H. F. Sniyth, Arch. I d . Hyg. Occup. Med., 8, 219(1953). (12) A. J. Lehman, Ass. Food Drug O$r., U. S. Qiturf. BUN..19,
87( 1955). (13) R. S. Harris, H. C. Hodge, E. A. Maynard, and H. J. Blanchet, Arch. Ind. Heulth, 13, 25% 1956). (14) J. McLaughlin, Jr., J. P. Marliac, M. J. Verrett, M. K. Mutchler, and 0. G . Fitzhugh, Toxicol. Appl. Plrarmucol., 5, 760 (1963). (15) D. Calley, J. Autian, and W. L. Guess, J . Pliurm. Sci., 55, I58( 1966). (16) J. Cornfield and N. Mantel, Amer. Stufist. Ass. J . . 45, 181 (1950). (17) C. S. Weil, Biometrics, 8, 249(1952). (18) R. E. Staples and V. L. Schnell, Stair? Techno/.,39, 61(1964). (19) H. Nishimura, “Chemistry and Prevention of Congenital Abnormalities,” Charles C Thomas, Springfield, Ill., 1964. (20) H. Bancroft, “Introduction to Biostatistics,” Harper & Row, New York, N. Y.,1963, chap. 15.
ACKNOWLEDGMENTS AND ADDRESSES Received March 29, 1971, from the Mrrterials ScieririJ Toxicology hboratorics, College of Deitfisfry and College of Pltarmicy, University of Tentiessee Medical Units, Memphis, T N 38103 Accepted for publication August 27, 1971. Presented at The Society of Toxicology Meeting, Washington, D. C., March 1971. Supported in part by Research Grant DE02944-02 from the National Institute of Dental Research, Bethesda, MD 20014 To whom inquiries should be directed.
*
Synthesis and NMR Spectral Characteristics of Bisnorargemonine Isomers CHUNG-MSIUNG C€IEN* and T. 0. SOINE’
~~~~
~~
structures, Ia and Jb, could have been considered but were rejected due t o a predictable nonconformity in their NMR spectra. However, it was of interest to synthesize la and lh, not only to verify the predicted NMR patterns but also to seek a practical synthetic route to provide these phenolic bases for projected oxidative coupling studies. The incidental provision of spectral and other data could also be of value in the future in assigning structures in the event that either or both of these diphenols are found to be naturally occurring, a not unlikely possibility. Key phrases [3Hisnorargemonine isomers-synthesis, NMR characPursuant to a suggestion by Stermitz’, i t is believed teristics 0 3,9-1~iliydroxy-2,8-dimethoxy-N-methylpavinane-synthesis, NMR characteristics 0 2,8-Dihydroxy-3,9-dimethoxy-N- appropriate to introduce a new type of nomenclature methylpavinane- synthesis, NMR characteristics 0NMR spectrosfor this ring system since further extension of the “arcopy -characteristics of bisnorargemonine isomers gemonine” nomenclature seems inadvisable if not impossible. Accordingly, it is proposed that the term “pavAbstract Two stl’uctural isomers of bisnorargemonine, 3.9-dihydroxy-2,8-dimethoxy-N-methylpavinane(lo) and 2,8-dihydroxy3,9-diniethoxy-N-mzthylpavinane(Ih), were synthesized employing the Pictet--Canis modification of the Bischler-Napieralski cyclization to construct the required isoquinoline intermediates. These were quaternized to the methiodides, followed by partial reduction to the N-niethyl-l.2-dihydroisoquinolines, which were then cyclized under acidic condilions to provide la and Ib. Comparison of the NMR spectra of lo and Ib with similar compounds revealed interesting aspects of the spectral properties pertaining to this ring system.
The recent synthesis of (*)-bisnorargemonine ( I , 2) confirmed Structure Ic assigned to it previously on the basis of its unique NMR spectrum (3). Two alternate
1 Private communication from Dr. F. Stcrmitz, Colorado State University, Fort Collins, Colo.. which forms the basis for the proposed nomenclature.
Vol. 61, No. I , January 1972 055
IIa, b
F’ %OR3
bR,
6R,
Va, b
IVa, b
H,PO,-HCOOH
boa-%: N-CH3
RlO
R3
OR4 Ma, b Scheme I-For
10
lI
12
0 1
Ia: R, = b = H , & = R,=CHJ I& R1= Rj uCH3, &-R, -H Ic: R, = R, = H, & = & -CH3 Id: R, =H, & I& R, -CH, Ie: % = H , Rl-R,-R,-CH3 R, = CH3; and b, RI = R3 = CH3, Rz
Compounds I1 + I X : a, RI = Rs = CH2Ph, R1 = (Ph = phenyl here and in all tables)
=
Rc = CHzPh
structures of intermediates involved in this sequence, VIIa and inane” with the numbering indicated in I be adopted VIIb were reduced with sodium borohydride in methanol to the for the tetracyclic ring system characteristic of these known N-methyl-] ,2,3,4-tetrahydroisoquinolines,VlIIa and VllIb, alkaloids. Under this system, Ia would be 3,9-dihydroxythe physical constants of which agreed with those synthesized by 2,8-dimethoxy-N-methylpavinane,Ib would be 2,8-diothers (8, 9) uia independent routes. Finally, partial reduction of VIIa and Vllh to the respective N-methyl-I ,2-dihydroisoquinolines, hydroxy-3,9-dimethoxy-N-methylpavinane, and Ic would IXa and IXb, by the sodium borohydride-pyridine method of be 2,9-dihydroxy- 3,8 - dimethoxy - N - methylpavinane. Barton er 01. (10) was followed by the acid-catalyzed cyclization of Other related alkaloids such as norargemonine (Id) and Battersby and Binks (1 l), which simultaneously cleaved the protecisonorargemonine (Ie) would be handled accordingly and tive benzyloxy groups to give the desired diphenols, Ia and Ib. acquire the names 9-hydroxy-2,3,8-trimethoxy-N-methyl- Table I gives the NMR data for all the intermediate compounds pavinane and 8-hydroxy-2,3,9-trimethoxy-N-methylpav- involved in the synthetic scheme. Assignments of each signal were made by comparison with similar series of compounds prepared inane, respectively. previously in the synthesis of Ic (2). Other physical data (i.e., UV
DISCUSSION The synthesis of Ia and Ib followed, essentially, the procedures developed for synthesis of Ic (1, 2). Scheme I outlines the key steps leading to la and Ib. The initially required amines. IIa and Ilb, were prepared as previously described (1, 2) by the method of Rosenmund er al. (4); the phenylacetic acids, Illa and Illb, were prepared by the methods of Douglas and Gulland ( 5 ) and Robinson and Sugasawa (6), respectively. Condensations between IIa and IVa and betaeen 116 and 1Vb provided the respective amides, Vn and Vb, which were readily aromatized to the isoquinolines, VIa and Vlb, by treatment with phosphorus oxychloride utilizing the Pictet-Gams variation of the Bischler-Napieralski cyclization (7). Quaternization of Vla and Vlb with methyl iodide yielded VIla and VIIb. To establish the
56
0Journal of Pharmaceurical Sciences
and IR; see Experimeiital section) are also in keeping with the structures expected. Combined column chromatography and preparative TLC were employed to isolate la and Ib from the reaction mixtures in 12 and 9% yields, respectively. Both la and I6 showed in their mass spectra a molecular ion at m / e 327, which has an elemental composition of CI9H2,NO4as revealed by corresponding high-resolution mass spectra*. The IR absorption of la at 3481 crn.-l and that of Ib at 3480 cm.-l confirmed the phenolic functions in these molecules. That both compounds are indeed 2,3,8,9-tetrasubstituted N-methylpavinanes The authors are indebted to Dr. Gene Sparrow, Central Research Laboratories, Minnesota Mining and Manufacturing Co., St. Paul, Minn., for these spectra. They were carried out on a CEC model 21-1 LO C high-resolution massspectrometer.
Table I-NMR
data’ for Va, Vb, VIa, VIb, VIIa, Vllb,
OCHzPh 4.85(s, 4H) 4.84(s, 4H) Vb d H z P h c 6 (17 c 3 ’ c4’ c6 c7 c3’ - 4.84 VIU 6.02 - 6.23 - 6.14 - 6.14 4.70 - 4.95 VIb ---OCHa-4CHzPhC6 ‘27 C3’ C4’ Ca G Ca’ - 4.61 VlIa 5.87 - 6 . 17 Va
VIIb
OCH3 6. I3(s, 6H) 6.09(s, 6H) 7 - O CHr-
-
6.02
-
-
6.23 4.51
--OCKa-------
c(
c 7
-
4.94
1x0,and IXb
c4’ 4.90 -
IXa
6.24
-
6.29
IXb
-
6.39
-
c4’
-
c 6
-
6.23 4.86
8-OCH3 6.83(s) 6.89(s) CS-H
5.56(s) 5.47(s) Ci-C Hz
1. W d , J3,4 = 6 Hz.)
C4’ 4.92
4.96(s)
-
4.96(s)
1.65(d, J3.4 = 5 . 7 Hz.) Ca-H and C4-H A B quartet 1 . 3 1 , 1.72(Js.4 = 6 . 8 Hz.) 1.40, 1.69(Ja.4 = 6 . 2 Hz.) C3-H(d of d) and C,-H(d) 3.84, 4.5qJ3.4 = 7.2Hz.,Ji.j = 1 . 2 Hz.) 3.92, 4.57(J3.4 = 7 . 3 Hz., J1.3 = 1 . 2 Hz.)
Ci- H
-0CHzPhc3’
--C(=O)--CHz6.516) 6.55(s) Ci-CHz
c 7
c3’
5.07
-
-
4.91
c4‘
4.87
5.51(t)
-
5.54(t)
+
N-CHa 5.52(s) 5.7qs) N-CHj
G-H
7.21(s)
3.64(s)
7.23(s)
3.74(s)
a Chemical shifts are given as T values. Compounds Vn, Vb. VIa, VIb, and VIIa were taken in CDCls; VIIb was taken in dimethyl sulfoxide-ds; and 1Xa and IXb were taken in pyridine-da.
was shown by the characteristic “triplet” absorption bands in their U V spectra. Thus, la absorbs at 285, 289, and 293 nm. and Ib absorbs at 285, 289, and 294 nm., both being very similar to those of the Argemone alkaloids (12). This is further substantiated by comparison of the mass spectra of la and Ib with that of Ic (Table 11). The major mode of fragmentation was the formation of the Nmethylisoquinoliniuin ion (X) ( m / e 190) from the molecular ion ( m/e 327), a fragmentation pattern characteristic of the ring system under consideration (1 3, 14). Upon close inspection, la-Ic showed a strong resemhlance with respect to other minor ions, suggesting that the disposition of hydroxy and methoxy groups does not significantly affect the fragmentation pattern of these isomeric diphenols. Examination of the NMR spectra of Ia and Ih (Table 111) reveals the symmetrical nature of these two molecules. The aromatic protons are paired into two singlets, suggesting that HI is identical with H7 in chemical environment as is H, with Hla. Similarly, the two methoxy groups are identical, and only one singlet of six protons was observed. Thus, all evidence points to Structures Ia and Ib for the compounds synthesized. After these two structural isomers of bisnorargemonine (Ic) were available, several interesting points began to emerge on comparison of their NMR spectra with those of other known compounds in the same series such as norargemonine (Id), isonorargemonine (Ie), argemonine (If), and 2,3,8,9-tetrahydroxy-N-rnethylpavinane(Ig). Compound Ig was originally prepared by demethylation of Ic (15) and isolated as its hydrochloride salt. By employing the same procedure, demethylation of If(see Experimenral) provided the hydrochloride of Ig, which was identical with the sample obtained from lc ( 1 5 ) . Since the free base form of Ig was rather unstable, the dimethyl sulfoxide-d6 solution of the hydrochloride salt in an NMR tube was neutralized directly by incremental addition of NaOD in D20, and the change in chemical shifts was observed. As illustrated in Fig. I , the chemical shifts of aromatic protons and N-methyl protons could be easily estimated at the point of neutralization because a maximum upfield shift of the N-methyl signal was reached. The values estimated in this manner are given in Table 111. For all compounds listed in Table 111, the singlet for the Nmethyl protons centers around T 7.65 for all practical purposes. This is probably due to the fact that the N-methyl group is rather isolated from the rest of the molecule (i.e., aromatic rings) where significant structural changes take place. By taking la and Ib as reference compounds, it is possible to assign the chemical shift for each methoxy group at different positions
on the ring. The methoxy groups at the Cz and C8 positions appear upfield by about 0.07-0.10 p.p.m. as compared to those at C, and C9. This may be rationalized as being due to the inductive effect of the C-N bond at the bridge-head, which is nearer to the methoxy groups at Ca, C9 than those at CZ,CS. The most interesting chemical shifts, however, are those of the aromatic protons. Since la, Ib, JA and Ig all possess a twofold axis of symmetry, the aromatic protons are paired into two singlets. If one assumes that the inductive effect of a bridge-head C-N bond influences the chemical shifts of aromatic protons, then H, and Hlo should be assigned to the low field singlet and HI and H7 t o the high field singlet. Furthermore, since the two aromatic rings in this type of structure are essentially independent of one another with respect to spin systems affecting NMR chemical shifts, a predictable additivity of spectra is observed. Thus, the spectrum of Ic could be considered as a combination of la and Ib, Idas a combination of Ia and If, and Ie as a combination of Ib and If (Fig. 2). Another consequence of this additive phenomenon is reflected in the constant range of upfield shift of a proton orrho to a hydroxyl group and a proton mefa to a hydroxyl group if one takes the tetramethoxy Compound lfas a reference standard. As shown in Table IV, protons orrho to a hydroxyl group invariably undergo a greater upfield shift than do protons mefa to a hydroxyl group. In Compound Ig, the combined effect of orrho and mefu upfield shifts is observed, and the observed values (0.25 and 0.29) agree quite well with the calculated value (0.26). Since both ranges of upfield shifts do not overlap, one could also take this as a criterion and thus make assignments foe each aromatic proton. The results obtained are essentially the same as those listed in Table Ill. The assumption was made in all the previous assignments that the inductive effect of a bridge-head C-N bond determined the chemical shift of the aromatic protons in the pavinane ring system. To confirm this, both Ia and I6 were incrementally converted into phenolate anions with NaOD and, at the same time, the change in chemical shift of the aromatic protons was observed (Fig. 3). If, without phenolic hydroxyl groups, served as a reference compound to compensate for solvent effects on chemical shifts. Highet and Highet (16) established that, on conversion to phenolate ions, the ensuing resonance effect generally causes the aromatic Table 11-Mass
_ _ ~ m/e---_ _ 327 190 328 326 312 311 191 177 176 175 162 137
7
Ia 16 Ic
X m/e190
Spectra of Ia-Ica
a
7 - 6 401001734 7 7 1 6 - 8 - 6 30100 7 2 5 6 5 1 5 - - 70 100 15 57 11 9 37 7 6 15 7 6
Relative abundance of ions larger than 5 %. Vol. 61, No. I , January 1972
057
7.6 7.5
7.4 I I
7.3
5
7.2
d
I I I
L
I
I
3.7 3.6
3.5 3.4
3.3
tL
I
I
I
1
0.5
1.0
night at room temperature. The benzene layer was then separated from the aqueous layer, and the latter was extracted twice with fresh benzene. The combined benzene solution was dried (anhydrous K2C01)and evaporated to give a brown oil. This oil (about 15.8 g.) was further purified by passing through a silica gel column (350 g., Baker 3405, 60-200 mesh), using benzene-thy1 acetate (20:5) as the eluting solvent (100 ml./fraction). Fractions 18-25 were combined and evaporated to give a colorless oil, which crystallized from absolute ethanol to yield 13.30 g. (79%) of Va as white needles, m.p. 95.5-97’; IR ~ : $ y lcm ~ ’-~ l .. 3322 (NH), 1639 (amideI), and 1507 (amide 11). And-Calc. for CJaH~sNO4: C, 73.18; H, 6.51; N, 2.59. Found: C, 72.97; H, 6.33; N, 2.33. N (3’ Benzyloxy 4’ methoxyphenylacetyl) @ methoxy@-(3-benzyloxy-4-methoxyphenyl)ethylamine (Vb)-3-Benzyloxy-C methoxyphenylacetic acid (IIIb) (13.82 g., 0.0508 mole) was converted t o its acid chloride (IVb) and condensed with 0.0508 mole (from 16.87 g. oxalate salt) of ~methoxy-fl-(3-benzyloxy-4-methoxypheny1)ethylamine (IIb) (2) as already described. The crude product mainly precipitated directly from the reaction mixture, but some was also obtained from the organic layer. The combined product was crystallized from 95% ethanol to yield 74% of Vb. Recrystallization from the same solvent gave fine white needles, rn.p. 102.5-104.5”; 1R :Lylail cm.-’: 3324 (NH), 1635 (amide I), and 1510 (amide 11). AnaL-Calc. for C ~ S H J ~ N O C,~ :73.18; H, 6.51; N, 2.59. Found: C, 73.11; H, 6.30; N, 2.56. l-(3’-Methoxy 4‘- benzyloxybenzyl) 6 methoxy 7-benzyloxyisoquinoline (VIa)-A mixture of 12.00 g. (0.022 mole) of Va
.
- -
- -
- -
-
-
- -
MOLES NaOD/MOLE ALKALOID
Figure 1 ---Estimationfor the chemical shi’s of the N-Me group and uromatic protons of Ig. Gradual addition of NaOD itr D 2 0 to the hydrochloride salt of Ig in dimethyl sulfoxide-de. protons to undergo an upfield shift, the range of upfield shift being greater for protons ortho to the hydroxy function than for protons meta to the hydroxy function. Based upon this, it is evident that the low field aromatic singlet in Ia, which shifted upfield with a greater range, should, therefore, belong to protons ortho to the phenolic function, i.e., H4and Hlo. In Ib, the high field singlet shifted with a greater range and hence is assigned to HI and H, which are ortho to phenolic groups. In both la and Ib, the low field singlet belongs to H4 and Hlowhich are adjacent to a C-N bridge-head. This firmly establishes the validity of the assumption made previously that assignments of ortho- or meta-positions of aromatic protons in this system can be made without resort to conversion to the phenolate form. Stermitz and Seiber (13) previously constructed similar curves for Ic-le. Once again, additivity was observed since the curve for Ic is a composite of la and Ib, Id is a composite of Ia and IA and Ie is a composite of Ih and If
EXPERIMENTAL3
-
N -(3’-Methoxy-4’-benzyloxyphenylacetyl)p - methoxy - @ -(3methoxy-4-benzyloxypheny1)ethylarnine (Va)-A mixture of 8.50 g. (0.031 mole) of 3-methoxy-4-benzyloxyphenylaceticacid (Illa) and 20 ml. of thionyl chloride in 150 ml. of chloroform was refluxed for 2 hr. The reaction mixture was concentrated, and the
I c = Ia-FIb
excess thionyl chloride was removed by repeated addition and evaporation of anhydrous toluene under vacuum. The oily acid chloride (IVa) was dissolved in 40 ml. of anhydrous benzene and added dropwise to a cooled (ice bath) and stirred mixture of 60 ml. of 1 0 z NaOH and 8.97 g. (0.031 mole) of p-methoxy-fl-(4-benzyloxy-3-methoxypheny1)ethylamine( H a ) (2) in 60 ml. of benzene. After the addition was completed, the stirring was continued overMelting points were taken with a Thomas-Hoover melting-point apparatus. U V spectra were measured in ethanolic solutions with a Cary model 14 spectrophotometer.I R spectra were determined with a PerkinElmer 2 3 7 8 grating IR spectrophotometer. N M R spectra were taken in suitable solvents, using tetramethylsilane as an internal standard, with a Varian Associates model A-60D N M R spectrometer and are recorded for all new compounds in Table I. Mass spectra were determined by a Hitachi Perkin-Elmer R M U - 6 D mass spectrometer. Elemental analyses were performed by M-H-W Laboratories, Garden City, Mich.
58
0Journal of Pharmaceutical
Sciences
Ie = IftIb
I 3.0
I 3.5
4.0
Figure 2-Aromatic region of la-Ie showing the additivity of spectra.
Table IV--Effect
Data" for Ia-Ig
Table III-NMR
of Hydroxyl Group on o- and m-Protonsa o-Protons
m-Protons ~
0.21 0.16 0.17 0.22 Id-I f 0.21 Ie-I f 0.18 Range 0.16-0.21 Average 0.19 Expected o m = 0.19 0.07 = 0.26 Observed Ig-I f = 0 . 2 5 and 0 . 2 9 Ia-I f Ib-I f Ic-I f
+
Ia Ib
Ic Id Ie
if
Ig
3.523.43 3.62 3.30 3.63 3.29 3.493.25 3.49 3.29 3.46 3.22 3.71 3.51
3.523.43 3.62 3.30 3.52 3.44 3.523.43 3.64 3.306 3.46 3.22 3.71 3.51
6.33 - 6.33 - 6 . 2 3 -6.23 - 6.27 6.34 6.356.286.35 -
7.64 7.63 7.65 7.65
6.32 6.23 6.32 6.23
7.64 7.67
_ - _ -
+
0.06 0.08 0.07 0.06 0.06 0.08 0.06-0.08 0.07
Upfield shifts in parts per million with respect to the If aromatic protons. using 5 methanol in chloroform as developing solvent. The zone was visualized under a U V lamp and eluted from the scraped band with methanol. The sample was crystallized from benzene as white needles, m.p. 146147.5"; U V Xg2H nm. (log c): 240 (4.71), 270 (3.79, shoulder), 281 (3.84), 315 (3.54), and 328 (3.60). Ana/.-Calc. for C32H29NO1: C, 78.18; H, 5.95; N, 2.85. Found: C, 78.30; H, 6.04; N, 2.67. 1 (4'-Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7-benzyloxyisoquinoliniumIodide (VI1a)-A mixture of 5 g. (0.0102 mole) of VIa and 50 ml. of methyl iodide in 30 ml. of dimethylformamide was refluxed for 1.5 hr. This was followed by another addition of 50 ml. of methyl iodide and continued reflux for 1.5 hr. Excess of methyl iodide was removed under vacuum to afford a brown liquid, which was diluted with anhydrous ether to precipitate a yellow solid. This solid was collected and washed thoroughly with anhydrous ether. Recrystallization from acetone yielded 4.0 g. (62 %) of VIIa as yellow prisms, m.p. 174.5-176"; U V XF2H nm. (log c): 259 (4.55),283 (3.62, shoulder), and 318 (3.78). Anal.-Calc. for Ca3Ha~INOl: C, 62.56; H, 5.09; N, 2.21. Found: C, 62.47; H, 4.92; N, 2.08. 1 (3' Benzyloxy 4' methoxybenzyl) 2 -methyl -6-bemyloxy7-methoxyisoquinolinium Iodide (V IIbFThe isoquinoline Vlb (3.70 g., 0.00753 mole) was treated with methyl iodide in dimethylformamide as already described to yield 82% of VIM. An analytical sample was obtained by recrystallization from acetone-methanol nm. (log t): 259 as yellow needles, m.p. 234-236'; U V": :A (4.68), 283 (3.70, shoulder), and 318 (3.97).
a All spectra were taken in dimethyl sulfoxide-ds and recorded in r . bValues for Compound Ie were taken from Reference 13; values for OCH3 and N-CHa signals are not presently available.
and 30 ml. of phosphorus oxychloride was refluxed in 200 ml. of toluene for 1.5 hr. The reaction mixture was evaporated under vacuum to afford a brown oily residue. This residue was dissolved in 200 ml. of chloroform and shaken with 100 ml. of 10% NaOH. Thechloroform layer was separated, washed with distilled water, dried (anhydrous K2C03), and evaporated to give a reddish-brown oil. This oil crystallized from lxnzene to give 6.20 g. (57 %) of VIa. Recrystallization from the same solvent yielded fine white needles, m.p. 177178.5"; UV hg2H nm. (log e): 240 (4.93), 270 (3.94, shoulder), 280(3.96), 314 ( 3 . 7 9 ,and 328 (3.70). Anal.--Calo. for CnHZ9NOI: C , 78.18; H, 5.95; N, 2.85. Found: C,78.33; H,6.25; N, 2.66. 1 (3' Benzyloxy -4'-methoxybenzyl)-6-benzyloxy-7-methoxyisoquinoline (V1b)-Compound Vb (19.9? g., 0.0368 mole) was treated with 50 ml. of phosphorus oxychloride and worked up as already described to give Vlb in 37% yield. An analytical sample was prepared by preparative TLC (silica gel F25,,Brinkmann, 2 mm.)
- -
-
- -
- -
- -
- -
-
-
-
4.0
If
Ia 3.9
3.8 3.7 3.6
3.4
3.1
-
}
1.0
MOLES
2.0
NaOD/MOLE ALKALOID
1.0
2.0
MOLES NaOD/MOLE ALKALOID
1.0 2.0 MOLES NaOD/MOLE ALKALOID
Figure 3- -Changein chemicalshifis of aromoric protons on conversion into phenolate ions. Vol. 61, No. I, January 1972
059
Anal.-Calc. for C 3 3 H d N 0 4 : C, 62.56; H, 5.09; N, 2.21. Found: C, 62.36; H, 5.02; N, 2.00. 1 (4' Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7 benzyloxy 1,2,3,4 tetrahydroisoquinoline (Vn1a)-Sodium borohydride (0.400 g.) was added portionwise to 0.208 g. (0.00328 mole) of VlJa in 40 ml. methanol and 0.5 ml. water. The resulting mixture was refluxed for 1 hr. After being cooled, methanol was removed under vacuum to give a white residue. Water (50 ml.) was added to this residue, and the resulting aqueous solution was extracted three times with ether. The combined ethereal solution was dried (anhydrous MgSO,) and evaporated t o yield a colorless residue. This residue was dissolved in petroleum ether (60-70") and cooled to afford 0.099 g. (6097,) of VIIIa as white needles, m.p. 92-93" [lit. (8) m.p. 94-95']. 1 (3' Benzyloxy 4' methoxybenzyl) 2 methyl 6 benzyloxy-7-methoxy-l,2,3,4-tetrahydroisoquinoline (VI1lb)-The methiodide VIM (0.21 1 g., 0.000333 mole) was reduced by sodium borohydride in aqueous methanol as described for Vllla. After the usual workup, the pale oil obtained was crystallized from ethanol-water to give VIllb (50%) as colorless needles, m.p. 9 5 9 7 " [lit. (8, 9) m.p. 9 3 5 9 4 . 5 "and 9697", respectively]. 1 (4' Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7-benzyloxy-1,2-dihydroisoquinoline (IXa) -To a suspension of 1.oO g. sodium borohydride in 40 ml. pyridine was added, portionwise, 3.63 g. (0.0057 mole) of Vlla. The mixture was shaken occasionally until complete solution was effected. A second batch of 0.800 g. of sodium borohydride was then added t o the solution, and shaking continued for 5 min. Ether was then added to the reaction mixture, followed by addition of water to decompose the resulting complex and excess sodium borohydride. The ether layer was separated, and the aqueous layer was extracted twice with ether. The combined ethereal extract was dried (anhydrous KzC03), and the solvent was removed by evaporation. Most of the pyridine remaining was removed under reduced pressure. The greenish-yellow oil obtained was dissolved in a few milliliters of absolute ethanol and cooled to afford 2.44 g. (84%) of 1Xa as white needles, m.p. 115-118". An analytical sample was prepared by two recrystallizations from the nm. (log c): 255 (4.05, same solvent, m.p. 115-118"; U V shoulder), 284 (3.78), and 337 (4.07). Anal.-Calc. for CSJH33NOd: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.22; H, 6.46; N, 2.84. 1 (3' Benzyloxy 4' methoxybenzyl) 2 methyl 6 benzyloxy-7-methoxy-1,2-dihydroisoquinotine (IXb)-Compound VIIb (3.00 g., 0.00471 mole) was reduced with sodium borohydride in pyridine in the same manner as described for VIIa. The greenish oil obtained was crystallized from absolute ethanol t o give 1Xb in 81% yield. Three recrystallizations from the same solvent gave fine white needles, m.p. 123-126"; U V nm. (loge): 254 (4.14, shoulder), 284 (3.63), and 333 (3.94). Atla/.-Calc. for C33H33NOI:C, 78.08; H, 6.55; N, 2.76. Found:C,77.80; H, 6.39; N, 2.74. 3,9-Dihydroxy-2,8-dimethoxy-iV-methylpavinane (1a)-A mixture of 2.12 g. (0.0042 mole) of IXa in 4.2 ml. of phosphoric acid (85%) and 10.5 ml. of formic acid (97%) was heated at 120" f o r 4 hr. under an atmosphere of nitrogen. The reaction mixture was cooled, diluted with 50 ml. of water, and extracted twice with 30 ml. of chloroform. The aqueous layer was separated and basified with 20% ammonium hydroxide solution. The resulting solution was then extracted with chloroform (6 X 50 ml.). The combined chloroform extract was dried (anhydrous MgS04) and evaporated under vacuum to give a brown residue (about 1.2 8.). This residue was dissolved in a few milliliters of benzene-methanol (10: I), and colorless prisms were obtained under standing a t room temperature. The crystals were filtered and washed with fresh solvent and ether, respectively, to give a white powder (0.35 g.). TLC analysis [silica gel, Eastman 6060, using benzene-methanol (3:2) as solvent] indicated that this residue contained one major component at RI 0.39 and two minor ones at RJ 0.46 and 0.52. The mixture was then recrystallized twice from methanol to give 0.170 g. (12.397,) of la as fine colorless needles, m.p. 250-251.5", R, 0.39; 1R vE!: cm.-l: 3481 (phenolic OH) and 1605 (C=C); U V' !:A : nm. (log e): 226 (4.10, shoulder), 285 (3.88), 289 (3.89), and 293 (3.85, shoulder). High-resolution mass spectra-M+ calc. for C1~H2~NO4: 327.14705. Found: 321.146. 2,8-Dihydroxy-3,9-dimethoxy-N-methylpa,ie (Ib)-A mixture of 1.833 g. (0.00371 mole) of 1Xb in 3.8 ml. of phosphoric acid
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(85.697,)and 9.5 ml. of formic acid (97%:)was heated under the same conditions as described for IXa. A similar workup procedure gave a brown residue (about 1.5 g.) from the basified reaction mixture. Silica gel TLC [benzene-methanol(3: 2)] indicated a major component a t Rf 0.55. This mixture was further fractionated by chromatography over a silica gel column (70 g., Baker 3405, 60-200 mesh) and eluted with a benzene-methanol (10: 1) solvent. Fractions of 25 ml. were collected and analyzed by TLC. Fractions 22-35 were found to contain spots with RJ 0.55. All of these fractions were combined and evaporated t o give a yellow residue. This residue was recrystallized from methanol-ether with cooling t o afford 0.057 g. of I b as yellow needles, m.p. 205-207". From the mother liquor, another 0.056 g. of I b was obtained by preparative TLC on a silica gel plate (Brinkmann F204, 2 mm.) using chloroform-ethyl acetate-methanol (2: 2 :I ) as the developing solvent. Compound I b appeared as a yellow zone under UV light. The yield of I b (0.113 g.)calculated from IXb was 9%; IR Y:.":. cm.-1: 3480 (phenolic OH) and 1601 (C=C); U V": :A nm. (log 6 ) : 226 (3.75, shoulder), 285 (3.51, shoulder), 289 (3.53), and 294 (3.49, shoulder). Highresolution mass spectra-M+ calc. for C19H21NOI: 327.14705. Found: 327.1476. 2,3,8,9-Tetrahydroxy-~-methylpavinane(Ig)-Compound If, 0.510 g. (0.00153 mole), and 3 g. of anhydrous aluminum chloride were mixed in 5 ml. of anhydrous xylene and heated a t 140-150" for 20 min., the temperature then being raised t o 180" for 5 min. The darkbrown solution was allowed to cool, and then ice and concentrated hydrochloric acid were added to decompose the complex. A pale-green crystalline precipitate formed. This precipitate was filtered and recrystallized from 10%hydrochloric acid t o give0.324 g. of Ig hydrochloride (64%) as white hexahedra, m.p. 213-216" [lit. (15) m.p. 209-213"l. The IR spectrum was identical with that of an authentic sample previously prepared in these laboratories (15), and a mixed meltingpoint determination showed no depression.
REFERENCES (1) C.-H. Chen, T. 0. Soine, and K. H. Lee, J. Pharm. Sci., 59, 152%1970). (2) Ibid., 60, 1634(1971). (3) T. 0. Soine and L. B. Kier, J. Pharm. Sci., 52, 1013(1963). (4) K. W. Rosenmund, M. Nothnagel, and H. Riesenfeldt, Ber., 60, 3921927). ( 5 ) R. L. Douglas and J. M. Gulland, J. Chem. SOC.,1931, 2893. (6j R. Robinson and S . Sugasawa, ihid., 1931, 3163. (7) W. M. Whaley and T. R. Govindachari, in "Organic Reactions," vol. 6, Wiley, New York, N. Y., 1951, p. 76 and references cited therein. (8) J. Kunitomo, J . Pharm. Soc. Jap., 81, 1257(1961). (9) R . Robinson and S. Sugasawa, J. Chem. Soc., 1933, 280. 110) D. H. R. Barton. R. H. Hesse, and G. W. Kirby, ibid., 1%5,'6379. ( 1 1) A. R. Battersby and R. Binks, ibid., 1955,2888. ( 1 2) R. P. K. Chan. J. C. Craig, R. H. F. Manske, and T. 0. Soine, Teirahedron, 23,4209(1967). (13) F. R . Stermitz and J. N. Seiber, J. Org. Chem., 31, 2925 ( 1966). (14) R. H. F. Manske, K. H. Shin, A. R. Battersby, and D. F. Shaw, Cart. J. Chem.,43,2183(1965). (15) L. B. Kier and T. 0. Soine, J. Pharm. Sci., 50, 321(1961). (16) R. J. Highet and P. R. Highet, J. Org. Chem., 30,902(1965).
ACKNOWLEDGMENTS AND ADDRESSES Received June 31, 1971, from the Department of Medicitld Chemistry, College of Pharmacy, Utrioersity of Mintresota, Minneapolis, M N 554.55 Accepted for publication August 30, 1971. Supported by Grant NB 08427 from the National Institutes of Health, U. S. Public Health Service, Bethesda, M D 20014 * Present address: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94122 A To whom inquiries should be directed.
REFERENCES ( I ) A. S. Trimble. B. S. Goldman, J. K. Yao, L. K. Kovats, and W. G . Bigeloa, Surgcry, 59, 857( 1966). (2) W. L. Guess, J. Jacob, and J. Autian, Drug Intel., 1, 120 (1967). ( 3 ) R. J. Jaeger and R. J. Rubin, Science, 170,460(1970). (4) W. L. Guess, S. Haberman, 1). F. Rowan, R. K. Bower, and J. Autian, A m w . J . Hosp. Pliurni., 24, 494(1967). ( 5 ) S. Haberman, W. 1.. Guess, D. E‘. Rowan, R. 0. Bowman, and R. K . Bower. S P E (Soc. Plusf. Eng.) J . , 24, 62( 1968). (6) K. K. Bower. S. Haberman, and P. D. Minton,J. Phurmacol. Erp. Thvr., 171, 314(1970). (7) “The Merck Index,” 8th ed., Merck & Co., Inc., Rahway, N. J., 1968. (8) H. C . Hodge. Proc. Soc. Exp. Biol. Mcd.. 53, 2q1943).
(9) C. B. Shaffer, C. P. Carpenter, and H. F. Smyth, Jr., J . Ind. Hyg. Toxicol., 27, 130( 1945).
(10) J. H. Draize, E. Alverez, M. F. Whitesell, G. Woodard, E. C. Hagan, and A. A. Nelson, J. Pliurmacol. E.up. Tlier., 93, 26 (1948). ( 1 1 ) C. P. Carpenter, C. S. Weil. and H. F. Sniyth, Arch. I d . Hyg. Occup. Med., 8, 219(1953). (12) A. J. Lehman, Ass. Food Drug O$r., U. S. Qiturf. BUN..19,
87( 1955). (13) R. S. Harris, H. C. Hodge, E. A. Maynard, and H. J. Blanchet, Arch. Ind. Heulth, 13, 25% 1956). (14) J. McLaughlin, Jr., J. P. Marliac, M. J. Verrett, M. K. Mutchler, and 0. G . Fitzhugh, Toxicol. Appl. Plrarmucol., 5, 760 (1963). (15) D. Calley, J. Autian, and W. L. Guess, J . Pliurm. Sci., 55, I58( 1966). (16) J. Cornfield and N. Mantel, Amer. Stufist. Ass. J . . 45, 181 (1950). (17) C. S. Weil, Biometrics, 8, 249(1952). (18) R. E. Staples and V. L. Schnell, Stair? Techno/.,39, 61(1964). (19) H. Nishimura, “Chemistry and Prevention of Congenital Abnormalities,” Charles C Thomas, Springfield, Ill., 1964. (20) H. Bancroft, “Introduction to Biostatistics,” Harper & Row, New York, N. Y.,1963, chap. 15.
ACKNOWLEDGMENTS AND ADDRESSES Received March 29, 1971, from the Mrrterials ScieririJ Toxicology hboratorics, College of Deitfisfry and College of Pltarmicy, University of Tentiessee Medical Units, Memphis, T N 38103 Accepted for publication August 27, 1971. Presented at The Society of Toxicology Meeting, Washington, D. C., March 1971. Supported in part by Research Grant DE02944-02 from the National Institute of Dental Research, Bethesda, MD 20014 To whom inquiries should be directed.
*
Synthesis and NMR Spectral Characteristics of Bisnorargemonine Isomers CHUNG-MSIUNG C€IEN* and T. 0. SOINE’
~~~~
~~
structures, Ia and Jb, could have been considered but were rejected due t o a predictable nonconformity in their NMR spectra. However, it was of interest to synthesize la and lh, not only to verify the predicted NMR patterns but also to seek a practical synthetic route to provide these phenolic bases for projected oxidative coupling studies. The incidental provision of spectral and other data could also be of value in the future in assigning structures in the event that either or both of these diphenols are found to be naturally occurring, a not unlikely possibility. Key phrases [3Hisnorargemonine isomers-synthesis, NMR characPursuant to a suggestion by Stermitz’, i t is believed teristics 0 3,9-1~iliydroxy-2,8-dimethoxy-N-methylpavinane-synthesis, NMR characteristics 0 2,8-Dihydroxy-3,9-dimethoxy-N- appropriate to introduce a new type of nomenclature methylpavinane- synthesis, NMR characteristics 0NMR spectrosfor this ring system since further extension of the “arcopy -characteristics of bisnorargemonine isomers gemonine” nomenclature seems inadvisable if not impossible. Accordingly, it is proposed that the term “pavAbstract Two stl’uctural isomers of bisnorargemonine, 3.9-dihydroxy-2,8-dimethoxy-N-methylpavinane(lo) and 2,8-dihydroxy3,9-diniethoxy-N-mzthylpavinane(Ih), were synthesized employing the Pictet--Canis modification of the Bischler-Napieralski cyclization to construct the required isoquinoline intermediates. These were quaternized to the methiodides, followed by partial reduction to the N-niethyl-l.2-dihydroisoquinolines, which were then cyclized under acidic condilions to provide la and Ib. Comparison of the NMR spectra of lo and Ib with similar compounds revealed interesting aspects of the spectral properties pertaining to this ring system.
The recent synthesis of (*)-bisnorargemonine ( I , 2) confirmed Structure Ic assigned to it previously on the basis of its unique NMR spectrum (3). Two alternate
1 Private communication from Dr. F. Stcrmitz, Colorado State University, Fort Collins, Colo.. which forms the basis for the proposed nomenclature.
Vol. 61, No. I , January 1972 055
IIa, b
F’ %OR3
bR,
6R,
Va, b
IVa, b
H,PO,-HCOOH
boa-%: N-CH3
RlO
R3
OR4 Ma, b Scheme I-For
10
lI
12
0 1
Ia: R, = b = H , & = R,=CHJ I& R1= Rj uCH3, &-R, -H Ic: R, = R, = H, & = & -CH3 Id: R, =H, & I& R, -CH, Ie: % = H , Rl-R,-R,-CH3 R, = CH3; and b, RI = R3 = CH3, Rz
Compounds I1 + I X : a, RI = Rs = CH2Ph, R1 = (Ph = phenyl here and in all tables)
=
Rc = CHzPh
structures of intermediates involved in this sequence, VIIa and inane” with the numbering indicated in I be adopted VIIb were reduced with sodium borohydride in methanol to the for the tetracyclic ring system characteristic of these known N-methyl-] ,2,3,4-tetrahydroisoquinolines,VlIIa and VllIb, alkaloids. Under this system, Ia would be 3,9-dihydroxythe physical constants of which agreed with those synthesized by 2,8-dimethoxy-N-methylpavinane,Ib would be 2,8-diothers (8, 9) uia independent routes. Finally, partial reduction of VIIa and Vllh to the respective N-methyl-I ,2-dihydroisoquinolines, hydroxy-3,9-dimethoxy-N-methylpavinane, and Ic would IXa and IXb, by the sodium borohydride-pyridine method of be 2,9-dihydroxy- 3,8 - dimethoxy - N - methylpavinane. Barton er 01. (10) was followed by the acid-catalyzed cyclization of Other related alkaloids such as norargemonine (Id) and Battersby and Binks (1 l), which simultaneously cleaved the protecisonorargemonine (Ie) would be handled accordingly and tive benzyloxy groups to give the desired diphenols, Ia and Ib. acquire the names 9-hydroxy-2,3,8-trimethoxy-N-methyl- Table I gives the NMR data for all the intermediate compounds pavinane and 8-hydroxy-2,3,9-trimethoxy-N-methylpav- involved in the synthetic scheme. Assignments of each signal were made by comparison with similar series of compounds prepared inane, respectively. previously in the synthesis of Ic (2). Other physical data (i.e., UV
DISCUSSION The synthesis of Ia and Ib followed, essentially, the procedures developed for synthesis of Ic (1, 2). Scheme I outlines the key steps leading to la and Ib. The initially required amines. IIa and Ilb, were prepared as previously described (1, 2) by the method of Rosenmund er al. (4); the phenylacetic acids, Illa and Illb, were prepared by the methods of Douglas and Gulland ( 5 ) and Robinson and Sugasawa (6), respectively. Condensations between IIa and IVa and betaeen 116 and 1Vb provided the respective amides, Vn and Vb, which were readily aromatized to the isoquinolines, VIa and Vlb, by treatment with phosphorus oxychloride utilizing the Pictet-Gams variation of the Bischler-Napieralski cyclization (7). Quaternization of Vla and Vlb with methyl iodide yielded VIla and VIIb. To establish the
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and IR; see Experimeiital section) are also in keeping with the structures expected. Combined column chromatography and preparative TLC were employed to isolate la and Ib from the reaction mixtures in 12 and 9% yields, respectively. Both la and I6 showed in their mass spectra a molecular ion at m / e 327, which has an elemental composition of CI9H2,NO4as revealed by corresponding high-resolution mass spectra*. The IR absorption of la at 3481 crn.-l and that of Ib at 3480 cm.-l confirmed the phenolic functions in these molecules. That both compounds are indeed 2,3,8,9-tetrasubstituted N-methylpavinanes The authors are indebted to Dr. Gene Sparrow, Central Research Laboratories, Minnesota Mining and Manufacturing Co., St. Paul, Minn., for these spectra. They were carried out on a CEC model 21-1 LO C high-resolution massspectrometer.
Table I-NMR
data’ for Va, Vb, VIa, VIb, VIIa, Vllb,
OCHzPh 4.85(s, 4H) 4.84(s, 4H) Vb d H z P h c 6 (17 c 3 ’ c4’ c6 c7 c3’ - 4.84 VIU 6.02 - 6.23 - 6.14 - 6.14 4.70 - 4.95 VIb ---OCHa-4CHzPhC6 ‘27 C3’ C4’ Ca G Ca’ - 4.61 VlIa 5.87 - 6 . 17 Va
VIIb
OCH3 6. I3(s, 6H) 6.09(s, 6H) 7 - O CHr-
-
6.02
-
-
6.23 4.51
--OCKa-------
c(
c 7
-
4.94
1x0,and IXb
c4’ 4.90 -
IXa
6.24
-
6.29
IXb
-
6.39
-
c4’
-
c 6
-
6.23 4.86
8-OCH3 6.83(s) 6.89(s) CS-H
5.56(s) 5.47(s) Ci-C Hz
1. W d , J3,4 = 6 Hz.)
C4’ 4.92
4.96(s)
-
4.96(s)
1.65(d, J3.4 = 5 . 7 Hz.) Ca-H and C4-H A B quartet 1 . 3 1 , 1.72(Js.4 = 6 . 8 Hz.) 1.40, 1.69(Ja.4 = 6 . 2 Hz.) C3-H(d of d) and C,-H(d) 3.84, 4.5qJ3.4 = 7.2Hz.,Ji.j = 1 . 2 Hz.) 3.92, 4.57(J3.4 = 7 . 3 Hz., J1.3 = 1 . 2 Hz.)
Ci- H
-0CHzPhc3’
--C(=O)--CHz6.516) 6.55(s) Ci-CHz
c 7
c3’
5.07
-
-
4.91
c4‘
4.87
5.51(t)
-
5.54(t)
+
N-CHa 5.52(s) 5.7qs) N-CHj
G-H
7.21(s)
3.64(s)
7.23(s)
3.74(s)
a Chemical shifts are given as T values. Compounds Vn, Vb. VIa, VIb, and VIIa were taken in CDCls; VIIb was taken in dimethyl sulfoxide-ds; and 1Xa and IXb were taken in pyridine-da.
was shown by the characteristic “triplet” absorption bands in their U V spectra. Thus, la absorbs at 285, 289, and 293 nm. and Ib absorbs at 285, 289, and 294 nm., both being very similar to those of the Argemone alkaloids (12). This is further substantiated by comparison of the mass spectra of la and Ib with that of Ic (Table 11). The major mode of fragmentation was the formation of the Nmethylisoquinoliniuin ion (X) ( m / e 190) from the molecular ion ( m/e 327), a fragmentation pattern characteristic of the ring system under consideration (1 3, 14). Upon close inspection, la-Ic showed a strong resemhlance with respect to other minor ions, suggesting that the disposition of hydroxy and methoxy groups does not significantly affect the fragmentation pattern of these isomeric diphenols. Examination of the NMR spectra of Ia and Ih (Table 111) reveals the symmetrical nature of these two molecules. The aromatic protons are paired into two singlets, suggesting that HI is identical with H7 in chemical environment as is H, with Hla. Similarly, the two methoxy groups are identical, and only one singlet of six protons was observed. Thus, all evidence points to Structures Ia and Ib for the compounds synthesized. After these two structural isomers of bisnorargemonine (Ic) were available, several interesting points began to emerge on comparison of their NMR spectra with those of other known compounds in the same series such as norargemonine (Id), isonorargemonine (Ie), argemonine (If), and 2,3,8,9-tetrahydroxy-N-rnethylpavinane(Ig). Compound Ig was originally prepared by demethylation of Ic (15) and isolated as its hydrochloride salt. By employing the same procedure, demethylation of If(see Experimenral) provided the hydrochloride of Ig, which was identical with the sample obtained from lc ( 1 5 ) . Since the free base form of Ig was rather unstable, the dimethyl sulfoxide-d6 solution of the hydrochloride salt in an NMR tube was neutralized directly by incremental addition of NaOD in D20, and the change in chemical shifts was observed. As illustrated in Fig. I , the chemical shifts of aromatic protons and N-methyl protons could be easily estimated at the point of neutralization because a maximum upfield shift of the N-methyl signal was reached. The values estimated in this manner are given in Table 111. For all compounds listed in Table 111, the singlet for the Nmethyl protons centers around T 7.65 for all practical purposes. This is probably due to the fact that the N-methyl group is rather isolated from the rest of the molecule (i.e., aromatic rings) where significant structural changes take place. By taking la and Ib as reference compounds, it is possible to assign the chemical shift for each methoxy group at different positions
on the ring. The methoxy groups at the Cz and C8 positions appear upfield by about 0.07-0.10 p.p.m. as compared to those at C, and C9. This may be rationalized as being due to the inductive effect of the C-N bond at the bridge-head, which is nearer to the methoxy groups at Ca, C9 than those at CZ,CS. The most interesting chemical shifts, however, are those of the aromatic protons. Since la, Ib, JA and Ig all possess a twofold axis of symmetry, the aromatic protons are paired into two singlets. If one assumes that the inductive effect of a bridge-head C-N bond influences the chemical shifts of aromatic protons, then H, and Hlo should be assigned to the low field singlet and HI and H7 t o the high field singlet. Furthermore, since the two aromatic rings in this type of structure are essentially independent of one another with respect to spin systems affecting NMR chemical shifts, a predictable additivity of spectra is observed. Thus, the spectrum of Ic could be considered as a combination of la and Ib, Idas a combination of Ia and If, and Ie as a combination of Ib and If (Fig. 2). Another consequence of this additive phenomenon is reflected in the constant range of upfield shift of a proton orrho to a hydroxyl group and a proton mefa to a hydroxyl group if one takes the tetramethoxy Compound lfas a reference standard. As shown in Table IV, protons orrho to a hydroxyl group invariably undergo a greater upfield shift than do protons mefa to a hydroxyl group. In Compound Ig, the combined effect of orrho and mefu upfield shifts is observed, and the observed values (0.25 and 0.29) agree quite well with the calculated value (0.26). Since both ranges of upfield shifts do not overlap, one could also take this as a criterion and thus make assignments foe each aromatic proton. The results obtained are essentially the same as those listed in Table Ill. The assumption was made in all the previous assignments that the inductive effect of a bridge-head C-N bond determined the chemical shift of the aromatic protons in the pavinane ring system. To confirm this, both Ia and I6 were incrementally converted into phenolate anions with NaOD and, at the same time, the change in chemical shift of the aromatic protons was observed (Fig. 3). If, without phenolic hydroxyl groups, served as a reference compound to compensate for solvent effects on chemical shifts. Highet and Highet (16) established that, on conversion to phenolate ions, the ensuing resonance effect generally causes the aromatic Table 11-Mass
_ _ ~ m/e---_ _ 327 190 328 326 312 311 191 177 176 175 162 137
7
Ia 16 Ic
X m/e190
Spectra of Ia-Ica
a
7 - 6 401001734 7 7 1 6 - 8 - 6 30100 7 2 5 6 5 1 5 - - 70 100 15 57 11 9 37 7 6 15 7 6
Relative abundance of ions larger than 5 %. Vol. 61, No. I , January 1972
057
7.6 7.5
7.4 I I
7.3
5
7.2
d
I I I
L
I
I
3.7 3.6
3.5 3.4
3.3
tL
I
I
I
1
0.5
1.0
night at room temperature. The benzene layer was then separated from the aqueous layer, and the latter was extracted twice with fresh benzene. The combined benzene solution was dried (anhydrous K2C01)and evaporated to give a brown oil. This oil (about 15.8 g.) was further purified by passing through a silica gel column (350 g., Baker 3405, 60-200 mesh), using benzene-thy1 acetate (20:5) as the eluting solvent (100 ml./fraction). Fractions 18-25 were combined and evaporated to give a colorless oil, which crystallized from absolute ethanol to yield 13.30 g. (79%) of Va as white needles, m.p. 95.5-97’; IR ~ : $ y lcm ~ ’-~ l .. 3322 (NH), 1639 (amideI), and 1507 (amide 11). And-Calc. for CJaH~sNO4: C, 73.18; H, 6.51; N, 2.59. Found: C, 72.97; H, 6.33; N, 2.33. N (3’ Benzyloxy 4’ methoxyphenylacetyl) @ methoxy@-(3-benzyloxy-4-methoxyphenyl)ethylamine (Vb)-3-Benzyloxy-C methoxyphenylacetic acid (IIIb) (13.82 g., 0.0508 mole) was converted t o its acid chloride (IVb) and condensed with 0.0508 mole (from 16.87 g. oxalate salt) of ~methoxy-fl-(3-benzyloxy-4-methoxypheny1)ethylamine (IIb) (2) as already described. The crude product mainly precipitated directly from the reaction mixture, but some was also obtained from the organic layer. The combined product was crystallized from 95% ethanol to yield 74% of Vb. Recrystallization from the same solvent gave fine white needles, rn.p. 102.5-104.5”; 1R :Lylail cm.-’: 3324 (NH), 1635 (amide I), and 1510 (amide 11). AnaL-Calc. for C ~ S H J ~ N O C,~ :73.18; H, 6.51; N, 2.59. Found: C, 73.11; H, 6.30; N, 2.56. l-(3’-Methoxy 4‘- benzyloxybenzyl) 6 methoxy 7-benzyloxyisoquinoline (VIa)-A mixture of 12.00 g. (0.022 mole) of Va
.
- -
- -
- -
-
-
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MOLES NaOD/MOLE ALKALOID
Figure 1 ---Estimationfor the chemical shi’s of the N-Me group and uromatic protons of Ig. Gradual addition of NaOD itr D 2 0 to the hydrochloride salt of Ig in dimethyl sulfoxide-de. protons to undergo an upfield shift, the range of upfield shift being greater for protons ortho to the hydroxy function than for protons meta to the hydroxy function. Based upon this, it is evident that the low field aromatic singlet in Ia, which shifted upfield with a greater range, should, therefore, belong to protons ortho to the phenolic function, i.e., H4and Hlo. In Ib, the high field singlet shifted with a greater range and hence is assigned to HI and H, which are ortho to phenolic groups. In both la and Ib, the low field singlet belongs to H4 and Hlowhich are adjacent to a C-N bridge-head. This firmly establishes the validity of the assumption made previously that assignments of ortho- or meta-positions of aromatic protons in this system can be made without resort to conversion to the phenolate form. Stermitz and Seiber (13) previously constructed similar curves for Ic-le. Once again, additivity was observed since the curve for Ic is a composite of la and Ib, Id is a composite of Ia and IA and Ie is a composite of Ih and If
EXPERIMENTAL3
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N -(3’-Methoxy-4’-benzyloxyphenylacetyl)p - methoxy - @ -(3methoxy-4-benzyloxypheny1)ethylarnine (Va)-A mixture of 8.50 g. (0.031 mole) of 3-methoxy-4-benzyloxyphenylaceticacid (Illa) and 20 ml. of thionyl chloride in 150 ml. of chloroform was refluxed for 2 hr. The reaction mixture was concentrated, and the
I c = Ia-FIb
excess thionyl chloride was removed by repeated addition and evaporation of anhydrous toluene under vacuum. The oily acid chloride (IVa) was dissolved in 40 ml. of anhydrous benzene and added dropwise to a cooled (ice bath) and stirred mixture of 60 ml. of 1 0 z NaOH and 8.97 g. (0.031 mole) of p-methoxy-fl-(4-benzyloxy-3-methoxypheny1)ethylamine( H a ) (2) in 60 ml. of benzene. After the addition was completed, the stirring was continued overMelting points were taken with a Thomas-Hoover melting-point apparatus. U V spectra were measured in ethanolic solutions with a Cary model 14 spectrophotometer.I R spectra were determined with a PerkinElmer 2 3 7 8 grating IR spectrophotometer. N M R spectra were taken in suitable solvents, using tetramethylsilane as an internal standard, with a Varian Associates model A-60D N M R spectrometer and are recorded for all new compounds in Table I. Mass spectra were determined by a Hitachi Perkin-Elmer R M U - 6 D mass spectrometer. Elemental analyses were performed by M-H-W Laboratories, Garden City, Mich.
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Ie = IftIb
I 3.0
I 3.5
4.0
Figure 2-Aromatic region of la-Ie showing the additivity of spectra.
Table IV--Effect
Data" for Ia-Ig
Table III-NMR
of Hydroxyl Group on o- and m-Protonsa o-Protons
m-Protons ~
0.21 0.16 0.17 0.22 Id-I f 0.21 Ie-I f 0.18 Range 0.16-0.21 Average 0.19 Expected o m = 0.19 0.07 = 0.26 Observed Ig-I f = 0 . 2 5 and 0 . 2 9 Ia-I f Ib-I f Ic-I f
+
Ia Ib
Ic Id Ie
if
Ig
3.523.43 3.62 3.30 3.63 3.29 3.493.25 3.49 3.29 3.46 3.22 3.71 3.51
3.523.43 3.62 3.30 3.52 3.44 3.523.43 3.64 3.306 3.46 3.22 3.71 3.51
6.33 - 6.33 - 6 . 2 3 -6.23 - 6.27 6.34 6.356.286.35 -
7.64 7.63 7.65 7.65
6.32 6.23 6.32 6.23
7.64 7.67
_ - _ -
+
0.06 0.08 0.07 0.06 0.06 0.08 0.06-0.08 0.07
Upfield shifts in parts per million with respect to the If aromatic protons. using 5 methanol in chloroform as developing solvent. The zone was visualized under a U V lamp and eluted from the scraped band with methanol. The sample was crystallized from benzene as white needles, m.p. 146147.5"; U V Xg2H nm. (log c): 240 (4.71), 270 (3.79, shoulder), 281 (3.84), 315 (3.54), and 328 (3.60). Ana/.-Calc. for C32H29NO1: C, 78.18; H, 5.95; N, 2.85. Found: C, 78.30; H, 6.04; N, 2.67. 1 (4'-Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7-benzyloxyisoquinoliniumIodide (VI1a)-A mixture of 5 g. (0.0102 mole) of VIa and 50 ml. of methyl iodide in 30 ml. of dimethylformamide was refluxed for 1.5 hr. This was followed by another addition of 50 ml. of methyl iodide and continued reflux for 1.5 hr. Excess of methyl iodide was removed under vacuum to afford a brown liquid, which was diluted with anhydrous ether to precipitate a yellow solid. This solid was collected and washed thoroughly with anhydrous ether. Recrystallization from acetone yielded 4.0 g. (62 %) of VIIa as yellow prisms, m.p. 174.5-176"; U V XF2H nm. (log c): 259 (4.55),283 (3.62, shoulder), and 318 (3.78). Anal.-Calc. for Ca3Ha~INOl: C, 62.56; H, 5.09; N, 2.21. Found: C, 62.47; H, 4.92; N, 2.08. 1 (3' Benzyloxy 4' methoxybenzyl) 2 -methyl -6-bemyloxy7-methoxyisoquinolinium Iodide (V IIbFThe isoquinoline Vlb (3.70 g., 0.00753 mole) was treated with methyl iodide in dimethylformamide as already described to yield 82% of VIM. An analytical sample was obtained by recrystallization from acetone-methanol nm. (log t): 259 as yellow needles, m.p. 234-236'; U V": :A (4.68), 283 (3.70, shoulder), and 318 (3.97).
a All spectra were taken in dimethyl sulfoxide-ds and recorded in r . bValues for Compound Ie were taken from Reference 13; values for OCH3 and N-CHa signals are not presently available.
and 30 ml. of phosphorus oxychloride was refluxed in 200 ml. of toluene for 1.5 hr. The reaction mixture was evaporated under vacuum to afford a brown oily residue. This residue was dissolved in 200 ml. of chloroform and shaken with 100 ml. of 10% NaOH. Thechloroform layer was separated, washed with distilled water, dried (anhydrous K2C03), and evaporated to give a reddish-brown oil. This oil crystallized from lxnzene to give 6.20 g. (57 %) of VIa. Recrystallization from the same solvent yielded fine white needles, m.p. 177178.5"; UV hg2H nm. (log e): 240 (4.93), 270 (3.94, shoulder), 280(3.96), 314 ( 3 . 7 9 ,and 328 (3.70). Anal.--Calo. for CnHZ9NOI: C , 78.18; H, 5.95; N, 2.85. Found: C,78.33; H,6.25; N, 2.66. 1 (3' Benzyloxy -4'-methoxybenzyl)-6-benzyloxy-7-methoxyisoquinoline (V1b)-Compound Vb (19.9? g., 0.0368 mole) was treated with 50 ml. of phosphorus oxychloride and worked up as already described to give Vlb in 37% yield. An analytical sample was prepared by preparative TLC (silica gel F25,,Brinkmann, 2 mm.)
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4.0
If
Ia 3.9
3.8 3.7 3.6
3.4
3.1
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}
1.0
MOLES
2.0
NaOD/MOLE ALKALOID
1.0
2.0
MOLES NaOD/MOLE ALKALOID
1.0 2.0 MOLES NaOD/MOLE ALKALOID
Figure 3- -Changein chemicalshifis of aromoric protons on conversion into phenolate ions. Vol. 61, No. I, January 1972
059
Anal.-Calc. for C 3 3 H d N 0 4 : C, 62.56; H, 5.09; N, 2.21. Found: C, 62.36; H, 5.02; N, 2.00. 1 (4' Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7 benzyloxy 1,2,3,4 tetrahydroisoquinoline (Vn1a)-Sodium borohydride (0.400 g.) was added portionwise to 0.208 g. (0.00328 mole) of VlJa in 40 ml. methanol and 0.5 ml. water. The resulting mixture was refluxed for 1 hr. After being cooled, methanol was removed under vacuum to give a white residue. Water (50 ml.) was added to this residue, and the resulting aqueous solution was extracted three times with ether. The combined ethereal solution was dried (anhydrous MgSO,) and evaporated t o yield a colorless residue. This residue was dissolved in petroleum ether (60-70") and cooled to afford 0.099 g. (6097,) of VIIIa as white needles, m.p. 92-93" [lit. (8) m.p. 94-95']. 1 (3' Benzyloxy 4' methoxybenzyl) 2 methyl 6 benzyloxy-7-methoxy-l,2,3,4-tetrahydroisoquinoline (VI1lb)-The methiodide VIM (0.21 1 g., 0.000333 mole) was reduced by sodium borohydride in aqueous methanol as described for Vllla. After the usual workup, the pale oil obtained was crystallized from ethanol-water to give VIllb (50%) as colorless needles, m.p. 9 5 9 7 " [lit. (8, 9) m.p. 9 3 5 9 4 . 5 "and 9697", respectively]. 1 (4' Benzyloxy 3' methoxybenzyl) 2 methyl 6 methoxy7-benzyloxy-1,2-dihydroisoquinoline (IXa) -To a suspension of 1.oO g. sodium borohydride in 40 ml. pyridine was added, portionwise, 3.63 g. (0.0057 mole) of Vlla. The mixture was shaken occasionally until complete solution was effected. A second batch of 0.800 g. of sodium borohydride was then added t o the solution, and shaking continued for 5 min. Ether was then added to the reaction mixture, followed by addition of water to decompose the resulting complex and excess sodium borohydride. The ether layer was separated, and the aqueous layer was extracted twice with ether. The combined ethereal extract was dried (anhydrous KzC03), and the solvent was removed by evaporation. Most of the pyridine remaining was removed under reduced pressure. The greenish-yellow oil obtained was dissolved in a few milliliters of absolute ethanol and cooled to afford 2.44 g. (84%) of 1Xa as white needles, m.p. 115-118". An analytical sample was prepared by two recrystallizations from the nm. (log c): 255 (4.05, same solvent, m.p. 115-118"; U V shoulder), 284 (3.78), and 337 (4.07). Anal.-Calc. for CSJH33NOd: C, 78.08; H, 6.55; N, 2.76. Found: C, 78.22; H, 6.46; N, 2.84. 1 (3' Benzyloxy 4' methoxybenzyl) 2 methyl 6 benzyloxy-7-methoxy-1,2-dihydroisoquinotine (IXb)-Compound VIIb (3.00 g., 0.00471 mole) was reduced with sodium borohydride in pyridine in the same manner as described for VIIa. The greenish oil obtained was crystallized from absolute ethanol t o give 1Xb in 81% yield. Three recrystallizations from the same solvent gave fine white needles, m.p. 123-126"; U V nm. (loge): 254 (4.14, shoulder), 284 (3.63), and 333 (3.94). Atla/.-Calc. for C33H33NOI:C, 78.08; H, 6.55; N, 2.76. Found:C,77.80; H, 6.39; N, 2.74. 3,9-Dihydroxy-2,8-dimethoxy-iV-methylpavinane (1a)-A mixture of 2.12 g. (0.0042 mole) of IXa in 4.2 ml. of phosphoric acid (85%) and 10.5 ml. of formic acid (97%) was heated at 120" f o r 4 hr. under an atmosphere of nitrogen. The reaction mixture was cooled, diluted with 50 ml. of water, and extracted twice with 30 ml. of chloroform. The aqueous layer was separated and basified with 20% ammonium hydroxide solution. The resulting solution was then extracted with chloroform (6 X 50 ml.). The combined chloroform extract was dried (anhydrous MgS04) and evaporated under vacuum to give a brown residue (about 1.2 8.). This residue was dissolved in a few milliliters of benzene-methanol (10: I), and colorless prisms were obtained under standing a t room temperature. The crystals were filtered and washed with fresh solvent and ether, respectively, to give a white powder (0.35 g.). TLC analysis [silica gel, Eastman 6060, using benzene-methanol (3:2) as solvent] indicated that this residue contained one major component at RI 0.39 and two minor ones at RJ 0.46 and 0.52. The mixture was then recrystallized twice from methanol to give 0.170 g. (12.397,) of la as fine colorless needles, m.p. 250-251.5", R, 0.39; 1R vE!: cm.-l: 3481 (phenolic OH) and 1605 (C=C); U V' !:A : nm. (log e): 226 (4.10, shoulder), 285 (3.88), 289 (3.89), and 293 (3.85, shoulder). High-resolution mass spectra-M+ calc. for C1~H2~NO4: 327.14705. Found: 321.146. 2,8-Dihydroxy-3,9-dimethoxy-N-methylpa,ie (Ib)-A mixture of 1.833 g. (0.00371 mole) of 1Xb in 3.8 ml. of phosphoric acid
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(85.697,)and 9.5 ml. of formic acid (97%:)was heated under the same conditions as described for IXa. A similar workup procedure gave a brown residue (about 1.5 g.) from the basified reaction mixture. Silica gel TLC [benzene-methanol(3: 2)] indicated a major component a t Rf 0.55. This mixture was further fractionated by chromatography over a silica gel column (70 g., Baker 3405, 60-200 mesh) and eluted with a benzene-methanol (10: 1) solvent. Fractions of 25 ml. were collected and analyzed by TLC. Fractions 22-35 were found to contain spots with RJ 0.55. All of these fractions were combined and evaporated t o give a yellow residue. This residue was recrystallized from methanol-ether with cooling t o afford 0.057 g. of I b as yellow needles, m.p. 205-207". From the mother liquor, another 0.056 g. of I b was obtained by preparative TLC on a silica gel plate (Brinkmann F204, 2 mm.) using chloroform-ethyl acetate-methanol (2: 2 :I ) as the developing solvent. Compound I b appeared as a yellow zone under UV light. The yield of I b (0.113 g.)calculated from IXb was 9%; IR Y:.":. cm.-1: 3480 (phenolic OH) and 1601 (C=C); U V": :A nm. (log 6 ) : 226 (3.75, shoulder), 285 (3.51, shoulder), 289 (3.53), and 294 (3.49, shoulder). Highresolution mass spectra-M+ calc. for C19H21NOI: 327.14705. Found: 327.1476. 2,3,8,9-Tetrahydroxy-~-methylpavinane(Ig)-Compound If, 0.510 g. (0.00153 mole), and 3 g. of anhydrous aluminum chloride were mixed in 5 ml. of anhydrous xylene and heated a t 140-150" for 20 min., the temperature then being raised t o 180" for 5 min. The darkbrown solution was allowed to cool, and then ice and concentrated hydrochloric acid were added to decompose the complex. A pale-green crystalline precipitate formed. This precipitate was filtered and recrystallized from 10%hydrochloric acid t o give0.324 g. of Ig hydrochloride (64%) as white hexahedra, m.p. 213-216" [lit. (15) m.p. 209-213"l. The IR spectrum was identical with that of an authentic sample previously prepared in these laboratories (15), and a mixed meltingpoint determination showed no depression.
REFERENCES (1) C.-H. Chen, T. 0. Soine, and K. H. Lee, J. Pharm. Sci., 59, 152%1970). (2) Ibid., 60, 1634(1971). (3) T. 0. Soine and L. B. Kier, J. Pharm. Sci., 52, 1013(1963). (4) K. W. Rosenmund, M. Nothnagel, and H. Riesenfeldt, Ber., 60, 3921927). ( 5 ) R. L. Douglas and J. M. Gulland, J. Chem. SOC.,1931, 2893. (6j R. Robinson and S . Sugasawa, ihid., 1931, 3163. (7) W. M. Whaley and T. R. Govindachari, in "Organic Reactions," vol. 6, Wiley, New York, N. Y., 1951, p. 76 and references cited therein. (8) J. Kunitomo, J . Pharm. Soc. Jap., 81, 1257(1961). (9) R . Robinson and S. Sugasawa, J. Chem. Soc., 1933, 280. 110) D. H. R. Barton. R. H. Hesse, and G. W. Kirby, ibid., 1%5,'6379. ( 1 1) A. R. Battersby and R. Binks, ibid., 1955,2888. ( 1 2) R. P. K. Chan. J. C. Craig, R. H. F. Manske, and T. 0. Soine, Teirahedron, 23,4209(1967). (13) F. R . Stermitz and J. N. Seiber, J. Org. Chem., 31, 2925 ( 1966). (14) R. H. F. Manske, K. H. Shin, A. R. Battersby, and D. F. Shaw, Cart. J. Chem.,43,2183(1965). (15) L. B. Kier and T. 0. Soine, J. Pharm. Sci., 50, 321(1961). (16) R. J. Highet and P. R. Highet, J. Org. Chem., 30,902(1965).
ACKNOWLEDGMENTS AND ADDRESSES Received June 31, 1971, from the Department of Medicitld Chemistry, College of Pharmacy, Utrioersity of Mintresota, Minneapolis, M N 554.55 Accepted for publication August 30, 1971. Supported by Grant NB 08427 from the National Institutes of Health, U. S. Public Health Service, Bethesda, M D 20014 * Present address: Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94122 A To whom inquiries should be directed.